RxFiles.ca - Trial Summary
L. Regier, B. Jensen -
July 13, 2009
RECORD - Rosiglitazone for cardiovascular outcomes in T2DM 1 If you are on metformin (MF)or a sulfonylurea (SU), is adding rosiglitazone (AVANDIA) inferior to moving to a combination of both MF and a SU? Background • Controversy and concern has surrounded the cardiovascular risk (CV) profile of rosiglitazone (AVANDIA) since GSK’s submission to the FDA2007 and Nissen and Wolski’s Meta-analysis2007 suggested increased CV events.2,3,4 {Concerns heightened as other PPAR αγ agonists under development failed due to CV problems in humans or bladder cancer in animals.}
Trial Background Data • Prospective, randomized, multicentre, open label, funded by GSK. Non-inferiority trial.
7428 screened, 4458 randomized
o 2228 already taking MF; 2230 already taking SU. 11 did not receive study med. (Apr 2001 – Dec 2008) o Inclusion: age 40-75; BMI >25kg/m2; already on max tolerated dose of MF or SU; A1C control less than optimal (>7-9%) o Exclusion: CV hospitalization in last 3 months, planned CV intervention, any heart failure (HF)
•
Treatment group vs Active Control group: (MFn=1117 or SUn=1103 + rosiglitazone) versus (MF + SU)n=2227 o o
•
Target A1C: ≤7.0%. Daily dose: Rosi: 4-8mg; MF: ≤2550mg; glibenclamide (= glyburide) ≤15mg; gliclazide ≤240mg; glimepiride ≤4mg. Rescue therapy (3rd agent added) if A1C ≥8.5%. If already on 3 agents including rosiglitazone, rosi stopped & insulin started.
n=4447, T2DM; agemean 57SU, ~60MF; A1C mean ~7.9%Ö7.4-7.9%; white; k 49-53%; weight 93kg MF, 85kg SU o background SU vs MF group: rate of -heart disease 20% vs 15%, -retinopathy ~13% vs ~7%; longer hx of T2DM 7.9 vs 6.2yrs o rosi. arms @baselineÖ5yrs vs control: ↑statins 18Ö55% vs19Ö46%;↑loop diuretic 3.1%bothÖ13% vs 8%; ↑weight 3.8-4.1kg
Results - over the mean 5.5 years of follow-up ,
n=2220
Clinical Endpoints * ** Rosiglitazone 14.46 % n=321 CV death or CV hosp (1°)* All-cause death 6.13 % CV death 2.70 % MI 2.88 % Stroke 2.07 % CV death, MI or stoke 6.94 % HF admission to hospital or death 2.75 % n=61 Fractures, All (From Table 7) 8.33 % n=185 Serious only Table 6
2.2 %
{modified ITT analysis: those who were randomized but never got study drug (11) not included.}
Active Control n=2227 ARR 14.50 % n=323 NS 7.04 % NS 3.19 % NS 2.51 % NS 2.83 % NS 7.41 % NS 1.30 % n=29 ↑ 1.45 % 5.30 % n=118 ↑ 3.03 % 1.6%
NS
NNT/NNH (95% CI) Comments 1°: HR: 0.99 (0.85-1.16) p = 0.9 {HR at 3.75yrs was 1.11 (0.93-1.32)}5 {to claim non-inferiority, upper limit of CI had to be ≤1.2} Subgroup analysis: trend for worse outcomes with rosiglitazone if previous ischemic heart disease (HR=1.26. CI:0.95-1.68) event rate was lower than predicted NNH=69 (44-162) study visit withdrawals: 7.2% person-yrs NNH=33 (22-66) Mostly upper & distal lower limb & l (RR:↑57%; ↑82% in l & 23% in k)
*Time to 1st event; **Other endpoints: no difference in malignancies, pneumonia; possible ↑ in non-serious but not serious macular edema. Per Protocol Analysis: HR: 1.02 (0.85-1.21) but excluded if 30days after transfer from dual treatment
Strengths, Limitations & Uncertainties Strengths: important clinical endpoints rather than surrogate ; reasonable duration ; best powered rosi trial to date Limitations: open label & funding source leave room for bias; limited statistical power for non1° endpoints; non-compliance or other bias a potential factor after publication of the Nissen meta- & interim RECORD analysis. • Dropout rate at trial’s end for the Tx & control groups is reported to be 40% & 50% respectively.6 Report does not provide these numbers but notes an excess of 32 people (1.4%) in the rosiglitazone group withdrew from treatment. 2.8% of patients were totally lost to follow-up. (Curiously, interim report stated ~ 10% lost to follow-up.)5 • Groups were treated differently (e.g. ↑ rate of statin and loop diuretic use in rosi arm may also be ↑dose of statin use?; higher rate of dropout in rosi arm after 2007 meta-analysis controversy); open label design together with the potential impact of a rosiglitazone controversy in the middle of the trial could affect trial outcome significantly. Of interest: the hazard ratio (HR) and Kaplan-Meier plots show a trend for worse outcome with rosiglitazone until the latter year of the trial. {The per-protocol analysis can not be used to assess this given complexity of study design (number of potential concomitant treatments and exclusion of any events occurring more than 30days after transfer from dual therapy.}
• SU dosing: quite high (e.g. gliclazide dose ≤240mg/day 2x higher than used in ADVANCE); {MF dose OK; 2550mg/day beneficial in UKPDS-34}; varied by local practice, adjustment only allowed after 8 wks • Would outcome results change if: a 3rd agent was added before the A1C was ≥8.5? What if insulin was the 2nd agent? • Uncertain is the complexity of a potential impact for two rosiglitazone arms & two active control arms (those with baseline SU vs baseline MF) on the results; this cannot be totally evaluated by subgroup analysis. For instance in the UKPDS-34 10yr, MF reduced CV & mortality risk overall in obese patients; however, when MF was added to SU patients, the risk ↑’d.7 This raises the issue of whether baseline group characteristics, choice & timing for drugs initiated could affect the outcomes.
Bottom Line: Ö We have UNCERTAINTY about somewhat REASSURING CV results & concerns about HF & fracture. • Adding rosiglitazone to patients on either MF or SU seems to be no worse on CV endpoints than combining MF & a SU. • Rosiglitazone may not ↑CV risk in patients who do not have HF, recent CV related hospital admission or ischemic heart • •
disease. Although somewhat reassuring, when the significant trial limitations are considered along with the results of previous trials, there is still uncertainty. {Remember we are still talking about uncertain harm; ideally we’d be talking about benefit.} Adding rosiglitazone/~5.5yrs: ↑ heart failure NNH=69, fractures NNH=33 & weight gain ~4kg more than MF or a SU but ↓hyperglycemia. Other considerations & unanswered questions: How would addition of rosiglitazone to a SU or MF compare to adding insulin to MF? How does rosiglitazone compare to pioglitazone (ACTOS)? (Pioglitazone has uncertain CV benefit based on the PROACTIVE trial so debate has been over whether neutral or beneficial for CV. Similar HF and fracture concerns)8 Does it matter which SU is used or what dose of SU is used? (Higher SU doses may be associated with hypoglycemia & adverse outcomes.9,10) Cost SK-Canada/100days: MF 2,550mg/day=$60; Gliclazide MR 60-240mg/day=$40-140; Rosiglitazone 4-8mg/day=$260-360
RxFiles.ca - Trial Summary
L. Regier, B. Jensen -
July 13, 2009
Update – July 2010: The RECORD trial has come under increasing criticism since publication. o E.g. an FDA researcher “found at least a dozen instances in which patients taking Avandia suffered serious heart problems that were not counted in the trial’s tally of adverse events” NY Times – Accessed 12Jul10http://www.nytimes.com/2010/07/13/health/policy/13avandia.html?_r=1 o This criticism is in the context of company data from 1999 showing signs of CV concerns relative to Pioglitazone; data that was not made public NY Times – Accessed 12Jul10http://www.nytimes.com/2010/07/13/health/policy/13avandia.html?_r=1 o Additional information FDA review – 13Jul10 FDA Briefing: http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/ucm218491.htm References See also: RxFiles Chart - Diabetes Landmark Trials & Links at: http://www.rxfiles.ca/rxfiles/uploads/documents/CHT-Diabetes-Landmark-Trials-Links.pdf RxFiles Rosiglitazone (Avandia) – CV Controversy Links: http://www.rxfiles.ca/rxfiles/uploads/documents/Rosiglitazone-CV-Controversy.htm RxFiles Chart – Oral Hypoglycemics: http://www.rxfiles.ca/rxfiles/uploads/documents/members/cht-diabetes.pdf (Available only to online subscribers or in RxFiles Drug Comparison Charts book - 7th Edition. www.RxFiles.ca
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Home PD, Pocock SJ, Beck-Nielsen H, Curtis PS, et al. Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial. Lancet. 2009 Jun 20;373(9681):2125-35. 2 GlaxoSmithKline. FDA Advisory Committee briefing document - cardiovascular safety of rosiglitazone. http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4308b1-01-sponsor-backgrounder.pdf Accessed July 11, 2009 3 Nissen SE, Wolski K. Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes. N Engl J Med. 2007 May 21. http://content.nejm.org/cgi/content/full/NEJMoa072761 4 Regier L, Jensen B. RxFiles Q&A: Rosiglitazone (Avandia) and Cardiovascular (CV) Risk. May 2007. Accessed July 11, 2009 at: http://www.rxfiles.ca/rxfiles/uploads/documents/Diabetes-Avandia-CV-Meta-Comments.pdf 5 Home PD, Pocock SJ, Beck-Nielsen H, Gomis R, et al. RECORD Study Group. Rosiglitazone evaluated for cardiovascular outcomes--an interim analysis. N Engl J Med. 2007;357:28-38. 6 Stiles S. ADA 2009: Avandia on the RECORD: No "Overall" CV Risk Increase, but Trial Remains Controversial. Medscape Heartwire. Accessed online July 11, 2009 at http://www.medscape.com/viewarticle/704038 7 (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet. 1998; 352:854-65. 8 Dormandy JA, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study. (PROspective pioglitAzone Clinical Trial In macroVascular Events): a RCT. Lancet. 2005; 366: 1279-1289. 9 Simpson SH, Majumdar SR, Tsuyuki RT, Eurich DT, Johnson JA. Dose-response relation between sulfonylurea drugs and mortality in type 2 diabetes mellitus: a population-based cohort study. CMAJ. 2006 Jan 17;174:169-74. 10 McAlister FA, Eurich DT, Majumdar SR, Johnson JA. The risk of heart failure in patients with type 2 diabetes treated with oral agent monotherapy. Eur J Heart Fail. 2008 Jul;10:703-8. Additional references: Home PD, Pocock SJ, Beck-Nielsen H, et al. Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes (RECORD): study design and protocol. Diabetologia. 2005 Sep;48(9):1726-35. Epub 2005 Jul 16. Home PD, Jones NP, Pocock SJ, et al. RECORD Study Group. Rosiglitazone RECORD study: glucose control outcomes at 18 months. Diabet Med. 2007 Jun;24(6):626-34. Home PD, Pocock SJ, Beck-Nielsen H, et al. Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial. Lancet 2009;373:2125-2135. Juurlink David N, Gomes Tara, Lipscombe Lorraine L, et al. Adverse cardiovascular events during treatment with pioglitazone and rosiglitazone: population based cohort study. BMJ 2009;339:b2942, doi: 10.1136/bmj.b2942 (Published 18 August 2009) Komajda M, Curtis P, Hanefeld M, et al.; RECORD Study Group. Effect of the addition of rosiglitazone to metformin or sulfonylureas versus metformin/sulfonylurea combination therapy on ambulatory blood pressure in people with type 2 diabetes: a randomized controlled trial (the RECORD study). Cardiovasc Diabetol. 2008 Apr 24;7:10. Komajda M, McMurray JJ, Beck-Nielsen H, et al. Heart failure events with rosiglitazone in type 2 diabetes: data from the RECORD clinical trial. Eur Heart J 2010; DOI: 10.1093/eurheartj/ehp604.
Prepared by L.oren Regier & Brent Jensen. The authors declare no conflicts of interest with any pharmaceutical companies. Thanks to those who contributed to this Q&A. Copyright 2009 RxFiles, Saskatoon Health Region; All Rights Reserved. DISCLAIMER: The content of this newsletter represents the research, experience and opinions of the authors and not those of the Board or Administration of SHR. Neither the authors nor SHR nor any other party who has been involved in the preparation or publication of this work warrants or represents that the information contained herein is accurate or complete, and they are not responsible for any errors or omissions or for the result obtained from the use of such information. Any use of the newsletter will imply acknowledgment of this disclaimer and release any responsibility of SHR , it employees, servants or agents. Readers are encouraged to confirm the information contained herein with other sources.
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